Journal article
Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL
Blood advances, Vol.1(12), pp.715-727
05/09/2017
DOI: 10.1182/bloodadvances.2016003632
PMCID: PMC5728051
PMID: 29296715
Abstract
Ibrutinib has generated remarkable responses in patients with chronic lymphocytic leukemia (CLL), including those with an unfavorable cytogenetic profile. However, patients develop resistance, with poor outcomes and no established treatment options. Mutations in BTK and PLCG2 have emerged as main mechanisms of drug resistance, but not all patients carry these mutations. Further understanding of mechanisms of resistance is urgently needed and will support rational development of new therapeutic strategies. To that end, we characterized the genomic profiles of serial samples from 9 patients with ibrutinib-relapsed disease, including 6 who had Richter transformation. Mutations, indels, copy-number aberrations, and loss of heterozygosity were assessed using next-generation sequencing and single-nucleotide polymorphism array. We found that 18p deletion (del(18p)), together with del(17p)/TP53 mutations, was present in 5 of 9 patients before ibrutinib therapy. In addition to BTKC481, we identified BTKT316A, a structurally novel mutation located in the SH2 domain of BTK. Minor BTK clones with low allele frequencies were captured in addition to major BTK clones. Although TP53 loss predisposes patients for relapse, clone size of TP53 loss may diminish during disease progression while mutant BTK clone expands. In patients who had Richter transformation, we found that the transformed cells were clonal descendants of circulating leukemia cells but continued to undergo evolution and drifts. Surprisingly, transformed lymphoma cells in tissue may acquire a different BTK mutation from that in the CLL leukemia cells. Collectively, these results provide insights into clonal evolution underlying ibrutinib relapse and prompt further investigation on genomic abnormalities that have clinical application potential.
Details
- Title: Subtitle
- Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL
- Creators
- Sabah Kadri - University of ChicagoJimmy Lee - University of ChicagoCarrie Fitzpatrick - University of ChicagoNatalie Galanina - University of ChicagoMadina Sukhanova - University of ChicagoGirish Venkataraman - University of ChicagoShruti Sharma - University of ChicagoBrad Long - University of ChicagoKristin Petras - University of ChicagoMegan Theissen - University of ChicagoMei Ming - University of ChicagoYuri Kobzev - University of ChicagoWenjun Kang - University of ChicagoAilin Guo - University of ChicagoWeige Wang - University of ChicagoNifang Niu - University of ChicagoHoward Weiner - University of ChicagoMichael Thirman - University of ChicagoWendy Stock - University of ChicagoSonali M. Smith - University of ChicagoChadi NabhanJeremy P. Segal - University of ChicagoPin Lu - University of ChicagoY. Lynn Wang - University of Chicago
- Resource Type
- Journal article
- Publication Details
- Blood advances, Vol.1(12), pp.715-727
- Publisher
- Amer Soc Hematology
- DOI
- 10.1182/bloodadvances.2016003632
- PMID
- 29296715
- PMCID
- PMC5728051
- ISSN
- 2473-9529
- eISSN
- 2473-9537
- Number of pages
- 13
- Language
- English
- Date published
- 05/09/2017
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701653102771
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